Distinguishing Japanese Spotted Fever and Scrub Typhus, Central Japan, 2004- 2015.
The typical signs and symptoms of JSF and ST are similar (e.g., fever, rash, and eschar), although in patients with ST, the frequency of rash varies from 14% to 93% and of eschar from 8% to 93% (9-13). For a few patients with JSF and ST, severe conditions develop (14-17). However, clinical information regarding JSF has been limited by lack of an appropriate case definition, lack of in-depth information, and studies involving small sample sizes (14,16). The clinical features observed in patients with JSF and ST are not comparable across studies because of the different enrollment criteria and nonstandardized case definitions. To clarify the clinical and epidemiologic characteristics of JSF and ST patients by using stringent laboratory confirmation methods and to identify the factors that distinguish the 2 diseases, we conducted a multicenter study in the southern Boso Peninsula in central Japan, an area of high JSF and ST endemicity. The study was approved by the institutional review boards of the Kameda Medical Center and the Awa Regional Medical Center.
Study Design and Setting
The southern Boso Peninsula is a predominantly rural mountainous region with a long coastline facing the Pacific Ocean and Tokyo Bay. According to the census, the total population in 2015 was 350,000 and 35.4% of the residents were [greater than or equal to] 65 years of age. We conducted prospective and retrospective case series reviews at 3 medical facilities: Kameda Medical Center (865 acute beds), Awa Regional Medical Center (149 beds), and Kameda Family Clinic-Tateyama (no beds).
Study Period and Entry Criteria
We prospectively enrolled patients from January 1, 2011, through December 31, 2015. We collected clinical, epidemiologic, and laboratory data from the patients who visited the study hospitals and exhibited signs and symptoms compatible with rickettsial disease. The patients were suspected to have rickettsial disease if they had any of the following clinical signs or symptoms without other apparent causes: fever, rash, eschar, respiratory symptoms, altered mental status, lymphadenopathy, neurologic abnormalities, systematic pain, chills/rigors, headache, or malaise. Using the same enrollment criteria, we also retrospectively collected data from patients who visited the study hospitals from January 1, 2004, through December 31, 2010, and who were not included in the prospective data collection. We used a standardized format to extract clinical and epidemiologic information from electronic medical records.
All blood samples were sent to a commercial laboratory (SRL, Inc., Tokyo) for an indirect immunofluorescence assay (IFA) to identify the O. tsutsugamushi serotypes Kato, Karp, and Gilliam; the antigens were provided by Denka Seiken Co., Ltd. If JSF was suspected, the samples were sent to the Chiba Prefectural Institute of Public Health for IFA to identify the O. tsutsugamushi serotypes Kato, Karp, Gilliam, Irie/Kawasaki, Hirano/Kuroki, and R. japonica (YH strain). The blood samples collected during 2009 and 2010 were also sent to the Ohara Research Laboratory (Fukushima City, Japan), and samples collected during 2014 were sent to the Mahara Institute of Medical Acarology (Anan, Japan) for an indirect immunoperoxidase assay to identify 6 O. tsutsugamushi serotypes (the previously mentioned 5 serotypes plus the serotype Shimokoshi), R. japonica (Aoki strain), and R. typhi (18). The type-specific whole rickettsial particles were used as antigens in the IFA and immunoperoxidase assays. Serum samples were diluted from 1:40 to 1:40,960 for immunoperoxidase assays and from 1:10 (or 20) to 1:10,240 for IFA. The titer was expressed as the reciprocal of the highest dilution. Nested PCR assays were performed to identify the 56-kDa antigen of O. tsutsugamushi and the 17-kDa genus-common antigen of R. japonica from eschars at the Chiba Prefectural Institute of Public Health (Chiba, Japan) or Kameda Medical Center (Kamogawa, Japan) (19,20).
Case Definitions and Data Collection
A patient's rickettsial status was defined as confirmed if the PCR result from the eschar was positive for any rickettsiae or if a [greater than or equal to] 4-fold increase in the IgM or IgG titer of IFA or immunoperoxidase assay was observed in paired serum samples (i.e., acute and convalescent phases). A patient's status that did not fulfill the criteria for confirmed was defined as probable if the IgM titer of IFA or immunoperoxidase assay was [greater than or equal to] 80 for JSF or ST. A patient's status was defined as possible if the clinical course was compatible with that of JSF or ST but the laboratory test results did not fulfill the criteria for either confirmed or probable. A patient was defined as having a nonrickettsial disease if a diagnosis of an infectious or noninfectious disease other than a rickettsial disease was confirmed. We excluded from analysis those patients who were classified as having possible cases or a diagnosis of murine typhus or concurrent JSF and ST infection.
Traditionally, in Japan, fever, rash, and eschar have been considered the triad of JSF and ST. We classified the triad into 3 categories: 1) "chief complaint" if any of the signs were the reason for the visit; 2) "upon history collection" if patients noticed the signs but had not complained until the physician asked; and 3) "physical exam" if the signs were objectively identified at the initial physical examination.
The clinical and epidemiologic characteristics of the patients were summarized and compared according to the 3 categories (i.e., JSF, ST, and nonrickettsial diseases). We used x2 or Fisher exact tests to compare characteristics of the patients by disease category. We computed odds ratios (ORs) with 95% CIs by using logistic regression models.
The patients' home addresses were geocoded and plotted on maps by using ArcGIS version 10.4.1 (Esri, Redlands, CA, USA). We calculated the population density and land use percentage within a radius of 500 m based on the census data and compared the 3 categories by using the Mann-Whitney U test. The Kulldorff scan statistics tool (SaTScan version 9.4.4) was used to identify the geographic clusters of JSF and ST (21). All tests were 2-tailed, and p<0.05 was considered statistically significant. All clinical data analyses were performed by using STATA version 13.0 (StataCorp LLC, College Station, Texas, USA).
A total of 661 patients were enrolled in the study: 303 by prospective and 358 by retrospective data collection. Overall, 42% of the patients were female, and the mean age was 60 years. Of the 50 patients whose eschars were tested by nested PCR, 8 were positive for R. japonica DNA and 29 were positive for O. tsutsugamushi DNA. The O. tsutsugamushi serotypes were identified in 22 patients; 16 were the Irie/Kawasaki type and 6 were the Hirano/Kuroki type. All patients were tested by an IFA at least 1 time, and paired blood samples were available for 304 (46%) patients. The median time from acute-phase sample collection to convalescent-phase sample collection was 14 days (interquartile range 11-17 days). Of the 304 patients, JSF was confirmed for 33 and ST was confirmed for 155. Of the 357 patients whose convalescentphase samples were unavailable, none had probable JSF and 35 had probable ST. Three patients who did not fulfill the serologic criteria for having a rickettsial disease but whose eschar was positive for O. tsutsugamushi DNA were confirmed as having ST. Two patients fulfilled the criteria for having both JSF and ST, and 1 patient was confirmed to have murine typhus. Overall, our analysis included 31 patients with JSF, 188 patients with ST, and 97 patients with nonrickettsial diseases (Figure 1). The final diagnoses of the nonrickettsial diseases are shown in online Technical Appendix Table 1 (https://wwwnc.cdc. gov/EID/article/24/9/17-1436-Techapp1.pdf).
Seasonal and Geographic Distributions
The seasonal distributions of JSF, ST, and nonrickettsial diseases are shown in Figure 2. All patients with JSF visited a medical facility during April-October; the numbers peaked slightly in July. Most (91%) patients with ST visited a medical facility in either November or December. No seasonal trend was observed for nonrickettsial diseases.
The geographic distributions are shown in Figure 3. We identified 1 JSF cluster (p<0.001) and 2 ST clusters (p = 0.013 and p = 0.041), and these clusters rarely overlapped. Patients with JSF and ST resided in less populated areas (population densities within a 500-m radius were 255/[km.sup.2] and 295/[km.sup.2], respectively) than patients with nonrickettsial diseases (904/[km.sup.2]; p<0.001). Patients with JSF and ST more frequently resided in wooded areas (proportions in forested area within a 500-m radius were 51% and 43%, respectively) than patients with nonrickettsial diseases (17%; p<0.001).
Demographic and Clinical Features
The baseline characteristics of the patients are summarized in Table 1. The proportion of female patients did not differ among the 3 groups. Patients with JSF and ST were older than patients with nonrickettsial diseases; among patients in the oldest age group, JSF occurred more frequently than ST. Patients with JSF and ST were more frequently exposed to the natural outdoor environment than were patients with nonrickettsial diseases.
Clinical characteristics of the patients are summarized in Table 2. The triad (i.e., fever, rash, and eschar) was commonly observed by physicians but not necessarily noticed by the patients. Fever was a primary sign; however, at the initial physical examination, body temperature was high in only 74% of patients with JSF and 73% with ST. Among patients who did not have a high body temperature at their initial physical examination, fever developed during hospitalization for 5 (71%) of 7 with JSF and 9 (38%) of 24 with ST. Although most patients had a rash, only 60% of patients with JSF and 44% with ST had noticed their rash. Moreover, only 45% of patients with JSF and 28% of patients with ST reported their rash. Most patients did not notice the presence of eschar.
During physical examination, patients with JSF had hypotension more frequently than patients with ST (OR 5.1, 95% CI 1.9-13.8), but no significant difference was observed in the frequency of tachycardia and tachypnea. Considerably higher proportions of patients with JSF and ST than with nonrickettsial diseases had a rash and eschar; the mean [+ or -] SD size of the eschar was smaller in patients with JSF (5.8 [+ or -] 2.1 mm) than in patients with ST (9.7 [+ or -] 5.6 mm; p = 0.024). Purpura, palmar/plantar rash, and lung involvement were more frequently observed in patients with JSF than in those with ST. Prevalence of lymphadenopathy did not differ among the groups.
Patients with JSF and ST were less likely than patients with nonrickettsial diseases to have leukocytosis and anemia but more likely to have elevated aspartate aminotransferase and lactate dehydrogenase levels, hyponatremia,
and urine occult blood (Table 3). Patients with JSF were more likely than patients with ST to have low platelet counts; elevated bilirubin, creatinine kinase, blood urea nitrogen, and creatinine levels; hyponatremia; and high Creactive protein.
Patients with JSF required hospitalization more frequently than did patients with ST; these associations did not change after we adjusted for age. Patients with JSF tended to visit a medical facility earlier than did patients in the other groups. JSF and ST were successfully treated in patients who received tetracycline; a 51-year-old patient receiving psychiatric care died of ST, but no patient died of JSF. The time to defervescence after treatment was longer for patients with JSF than for patients with ST.
By using standardized laboratory definitions for diagnosis, we determined that the clinical and epidemiologic characteristics of JSF and ST in Japan differed by seasonality, geographic distribution, physical signs, and severity. JSF and ST showed distinct seasonal patterns. JSF occurred during April-October and peaked slightly in July, whereas most ST occurred during November-December. JSF and ST were distributed in less populated and more wooded areas, although their geographic clusters rarely overlapped. Patients with JSF were more likely than patients with ST to have purpura, palmar/plantar rash, and organ damage and to be hospitalized.
The different seasonal distribution of JSF and ST observed in our study can be explained by the ecology of the vectors (3,22) as follows: 1) Haemaphysalis flava and H. longicornis ticks, which transmit R. japonica, are active from spring until autumn in Chiba (23); 2) Leptotorombidium scutellare mites, which transmit the Irie/Kawasaki (and Hirano/Kuroki) serotypes of O. tsutsugamushi, are active in autumn and early winter (24) and unable to survive the winter; and 3) L. pallidum mites, which transmit the Karp and Gilliam serotypes of O. tsutsugamushi, are active from October through May (24). The difference in geographic distributions of JSF and ST may also be explained by the different distribution of the reservoirs in our study settings. Sika deer are wild hosts of ticks, and their distribution overlaps with that of ticks (25). The cluster of JSF identified in our study overlapped with the distribution of sika deer and Reeves's muntjacs, which are related to sika deer (26,27). In contrast, the field rat, which is the primary host of the Leptotrombidium mite, is spreading throughout this area, which may explain the wide distribution of ST. Although our data are limited, similar patterns (i.e., the clustering of JSF and relatively wide distribution of ST) were also observed in other prefectures (28,29). Further studies are needed to establish the temporal and geographic associations among the vectors, reservoirs, and rickettsial pathogens.
Although the clinical features of patients in this study with JSF and ST were similar, some clinical findings were characteristic of JSF. Patients with JSF more frequently had rashes on the palms/soles, purpura, and small eschars. Moreover, the following severe conditions occurred more frequently among patients with JSF than among those with ST: hypotension, low platelet counts, and increased creatinine levels. Rickettsiae invade and proliferate within vascular endothelial cells and cause a vasculitis-like systemic disease (30). In a study by Tai et al., cytokine and chemokine levels were higher in patients with JSF than in patients with ST, but no significant association was observed between cytokine levels and the clinical severity of disease (17). Although previous human and animal model studies have revealed the pathogenic mechanisms of severe rickettsial infections (31-32), the mechanisms of severe JSF remain not fully understood. Of note, the clinical severity of ST may differ according to the Orientia serotype. According to a systematic review, the mortality rate from ST substantially varied according to patients' age, co-occurring conditions, and regional Rickettsia strains (33). Our findings of ST in regions where Irie/Kawasaki type and Hirano/ Kuroki type are endemic may not be directly applicable to other settings in which other serotypes are endemic, such as Akita and Niigata in northern Japan.
Fever has been considered one of the typical signs of JSF and ST. Most patients in our study had a high body temperature during the clinical course of their illness; however, fever was not apparent at the time of initial physical examination for 26% of patients with JSF and 27% of patients with ST. Although rash and eschar were commonly observed by the physicians, more than half of the patients did not notice these signs. Consequently, 33% of the patients with JSF and 34% of the patients with ST received incorrect diagnoses during their first medical visit. Furthermore, fewer clinicians were aware of JSF than of ST (34). These findings indicate that a substantial number of rickettsial diseases may be underdiagnosed in Japan.
Because of the difficulties associated with locating patients to collect blood samples during the convalescent phase of illness, previous studies have relied on laboratory confirmation that uses acute-phase samples with variable cutoff IgM titers without considering local endemicity, which may have resulted in misclassification (35). In this study, we used the IFA or immunoperoxidase IgM titer of [greater than or equal to] 80 as a cutoff for the diagnosis of JSF and ST for patients for whom convalescent-phase samples were unavailable. To determine the optimum cutoff titer in our setting, we collected blood samples from patients with nonrickettsial diseases and confirmed that the highest IgM titer for R. japonica was <20 and that for O. tsutsugamushi was 10 (online Technical Appendix Table 2). Therefore, our diagnostic criteria must be very specific.
During the acute phase of the disease, sensitivity of the IFA is quite low; in our study, an elevated IgM titer by IFA was observed in the acute-phase samples of only 2 (6.5%) of 31 patients with JSF and 73 (38.8%) of 188 patients with ST. Hence, physicians may overlook these diseases if their diagnosis relies on IgM titer by IFA during the early phase. Furthermore, the ST serotypes affect the sensitivity of the IFA. In our study, of the 22 patients for whom serotype was identified, 16 serotypes were Irie/Kawasaki and 6 serotypes were Hirano/Kuroki. In Japan, health insurance covers IFAs for the standard serotypes Kato, Karp, and Gilliam only but not for serotypes Irie/Kawasaki and Hirano/ Kuroki, which may not be cross-reactive to the standard serotypes (22). In our study population, use of IFAs to test for the standard serotypes could have led to underdiagnosis of ST for [approximately equal to] 5% of the patients because 2 patients with the Irie/Kawasaki and Hirano/Kuroki serotypes did not react to any of the standard serotypes.
Our study has limitations because we did not include the other 2 hospitals in the southern Boso Peninsula. However, our study sites are the only medical facilities in the district that have infectious disease specialists. Most patients with acute disease and fever in this district are expected to visit our clinic and hospitals. Thus, we believe that the effect of selection bias was minimal. Because our study is a combined prospective and retrospective case-series, the quality of the information may have differed between the prospectively and the retrospectively identified patients. However, we used an identical case definition throughout the study, and further analyses indicated that the clinical and epidemiologic characteristics did not differ between 2 groups (online Technical Appendix Table 3).
In conclusion, although JSF and ST share similar clinical features, in Japan the 2 diseases differ in seasonality, geographic distribution, physical signs, and severity. Patients with rickettsial diseases often do not notice their rash and eschar, and the sensitivity of the serologic test can be low during the acute phase of illness. A substantial number of rickettsial diseases may be underdiagnosed.
DOI: https://doi.org/ 10.3201/eid2409.171436
We thank the clinical laboratory staff at Kameda Medical Center and Takeshi Kimura and Yasuhisa Matsushita for collecting the data at the Awa Regional Medical Center.
This study was funded by the Kameda Medical Center; grants from the Japan Ministry of Health, Labour and Welfare (H21-Shinkou-Ippan-006 and H24-Shinkou-Ippan-008); and Grants-in-Aid for Scientific Research (Japan Society for the Promotion of Science).
Dr. Sando is a general physician at Kameda Medical Center, Kamogawa, Japan, and a postgraduate at Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. His primary research interests include rickettsial diseases such as ST and JSF.
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Eiichiro Sando, Motoi Suzuki, Shungo Katoh, Hiromi Fujita, Masakatsu Taira, Makito Yaegashi, Koya Ariyoshi
Author affiliations: Nagasaki University, Nagasaki, Japan (E. Sando, M. Suzuki, S. Katoh, K. Ariyoshi); Kameda Medical Center, Kamogawa, Japan (E. Sando, M. Yaegashi); Mahara Institute of Medical Acarology, Anan, Japan (H. Fujita); Chiba Prefectural Institute of Public Health, Chiba, Japan (M. Taira)
Address for correspondence: Motoi Suzuki, Nagasaki University, Department of Clinical Medicine, Institute of Tropical Medicine, Sakamoto 1-12-4, Nagasaki, 852-8523, Japan; email: email@example.com
Caption: Figure 1. Numbers of patients with rickettsial or nonrickettsial diseases, Japan, 2004-2015. Of 43 patients tested by immunofluorescence and immunoperoxidase assays, 4 fulfilled the criteria for having confirmed JSF, 7 for confirmed ST, and 7 for probable ST. Gray shading indicates the cases included in the main analysis. JSF, Japanese spotted fever; MT, murine typhus; non-R, nonrickettsial diseases; ST, scrub typhus.
Caption: Figure 2. Number of patients with Japanese spotted fever, scrub typhus, and nonrickettsial diseases, central Japan, by month, 2004-2015.
Caption: Figure 3. Geographic distribution and clusters of JSF and ST, Japan, 2004-2015. A) JSF; B) ST; C) geographic clusters of JSF and ST; D) locations of study facilities. White diamonds (JSF) and circles (ST) represent the locations of each patient's address. Shaded circles (red, JSF; blue, ST) represent statistically significant spatial clusters (p<0.05). The geographic distribution of the patients with nonrickettsial diseases, which were used for the cluster analysis as the reference, is shown in the Technical Appendix Figure (https:// wwwnc.cdc.gov/EID/article/24/9/17-1436-Techapp1.pdf). ARMEC, Awa Regional Medical Center; JSF, Japanese spotted fever; KFCT, Kameda Family Clinic Tateyama; KMC, Kameda Medical Center; ST, scrub typhus.
Table 1. Baseline characteristics of patients with JSF, ST, and nonrickettsial diseases, central Japan, 2004-2015 * Characteristic JSF, ST, Non-R, no. (%), no. (%), no. (%), n = 31 n = 188 n = 97 Female sex 16 (52) 85 (45) 35 (36) Age, y, mean (SD) 73 (10) 65 (15) 57 (20) Age group, y [less than or equal to] 54 1 (3) 29 (15) 43 (44) 55-64 7 (23) 48 (26) 14 (14) 65-74 7 (23) 56 (30) 13 (13) >75 16 (52) 55 (29) 27 (28) No exposure 1 (3) 18 (12) 32 (46) Living in/ 12 (40) 58 (38) 16 (23) stepped into mountainous areas Stepped into a 1 (3) 12 (8) 3 (4) bush Farming 16 (53) 65 (42) 14 (20) Characteristic JSF vs. non-R ([dagger]) OR (95% CI) p value Female sex 1.9 (0.8-4.3) 0.127 Age, y, mean (SD) Age group, y [less than or equal to] 54 Reference 55-64 21.5 (2.4-190.3) 0.006 65-74 23.2 (2.6-205.9) 0.005 >75 25.5 (3.2-203.3) 0.002 No exposure Reference Living in/ 24.0 (2.9-201.2) 0.003 stepped into mountainous areas Stepped into a 10.7 (0.5-217.2) 0.124 bush Farming 36.6 (4.4-303.4) 0.001 Characteristic ST vs. non-R ([dagger]) OR (95% CI) p value Female sex 1.5 (0.9-2.4) 0.14 Age, y, mean (SD) Age group, y [less than or equal to] 54 Reference 55-64 5.1 (2.4-10.9) <0.001 65-74 6.4 (3.0-13.7) <0.001 >75 3.0 (1.6-5.8) 0.001 No exposure Reference Living in/ 6.4 (2.9-14.3) <0.001 stepped into mountainous areas Stepped into a 7.1 (1.8-28.6) 0.006 bush Farming 8.3 (3.6-18.7) <0.001 Characteristic JSF vs. ST ([double dagger]) OR (95% CI) p value Female sex 1.3 (0.6-2.8) 0.509 Age, y, mean (SD) Age group, y [less than or equal to] 54 Reference 55-64 4.2 (0.5-36.1) 0.188 65-74 3.6 (0.4-30.9) 0.239 >75 8.4 (1.1-66.8) 0.043 No exposure Reference Living in/ 3.7 (0.5-30.6) 0.162 stepped into mountainous areas Stepped into a 1.5 (0.1-26.4) 0.162 bush Farming 4.4 (0.5-35.7) 0.162 * JSF, Japanese spotted fever; non-R, nonrickettsial diseases; OR, odds ratio; ST, scrub typhus. ([dagger]) Non-R reference. ([double dagger]) ST reference. Table 2. Clinical characteristics of patients with JSF, ST, and nonrickettsial diseases, central Japan, 2004-2015 * Characteristic JSF, ST, Non-R, no. (%), no. (%), no. (%), n = 31 n = 188 n = 97 Chief complaint Fever 26 (84) 135 (72) 78 (80) Rash 14 (45) 52 (28) 17 (18) Eschar 0 (0) 5 (3) 1 (1) Headache 1 (3) 29 (15) 5 (5) Fatigue 3 (10) 35 (19) 6 (6) At history collection Fever 27 (87) 148 (82) 81 (84) Rash 18 (60) 74 (44) 24 (26) Eschar 1 (4) 20 (12) 5 (6) Headache 4 (25) 75 (56) 27 (59) Fatigue 17 (94) 97 (84) 32 (94) Physical examination findings BT >37.5[degrees]C 23 (74) 132 (73) 53 (59) Hypotension ([paragraph]) 8 (26) 12 (6) 5 (5) Heart rate 2 (7) 13 (8) 6 (7) >120 bpm Respiratory rate 13 (54) 40 (39) 23 (45) >20/min Altered mental 5 (16) 14 (7) 15 (15) status Rash 30 (100) 181 (96) 52 (57) Localized 0 3 (2) 6 (12) Purpura 11 (44) 4 (2) 7 (8) Palms/soles 21 (84) 13 (7) 4 (5) Eschar 24 (89) 163 (87) 18 (22) Lung involv # 8 (26) 21 (11) 9 (9) Characteristic JSF vs. non-R ([dagger]) OR (95% CI) p value Chief complaint Fever 1.3 (0.4-3.7) 0.668 Rash 3.9 (1.6-9.3) 0.003 Eschar Not applicable 1.000 ([section]) Headache 0.6 (0.1-5.5) 0.661 Fatigue 1.6 (0.4-6.9) 0.511 At history collection Fever 1.3 (0.4-4.1) 0.712 Rash 4.3 (1.8-10.1) 0.001 Eschar 0.6 (0.1-5.5) 0.664 Headache 0.2 (0.1-0.8) 0.026 Fatigue 1.1 (0.1-12.6) 0.962 Physical examination findings BT >37.5[degrees]C 2.0 (0.8-5.0) 0.132 Hypotension ([paragraph]) 6.4 (1.9-21.4) 0.003 Heart rate 0.9 (0.2-4.9) 0.942 >120 bpm Respiratory rate 1.4 (0.5-3.8) 0.464 >20/min Altered mental 1.1 (0.3-3.2) 0.929 status Rash Not applicable <0.001 ([section]) Localized Not applicable 0.079 ([section]) Purpura 8.9 (2.9- 26.8) <0.001 Palms/soles 101.1 0.001 (23.3- 438.4) Eschar 28.0 <0.001 (7.6- 103.7) Lung involv # 3.4 (1.2-9.8) 0.023 Characteristic ST vs. non-R ([dagger]) OR (95% CI) p value Chief complaint Fever 0.6 (0.3-1.1) 0.115 Rash 1.8 (1.0-3.3) 0.06 Eschar 2.6 (0.3-22.8) 0.382 Headache 3.4 (1.3-9.0) 0.016 Fatigue 3.5 (1.4-8.6) 0.007 At history collection Fever 0.8 (0.4-1.6) 0.586 Rash 2.2 (1.3-3.8) 0.099 Eschar 2.1 (0.8-5.9) 0.141 Headache 0.9 (0.5-1.8) 0.748 Fatigue 0.3 (0.1-1.4) 0.138 Physical examination findings BT >37.5[degrees]C 1.9 (1.1-3.2) 0.02 Hypotension ([paragraph]) 1.3 (0.4-3.7) 0.679 Heart rate 1.2 (0.4-3.2) 0.777 >120 bpm Respiratory rate 0.8 (0.4-1.5) 0.457 >20/min Altered mental 0.4 (0.2-1.0) 0.038 status Rash 19.4 (8.2-45.9) <0.001 Localized 0.1 (0-0.5) 0.004 Purpura 0.2 (0.1-0.9) 0.028 Palms/soles 1.4 (0.5-4.6) 0.537 Eschar 23.8 <0.001 (12.1-46.8) Lung involv # 1.2 (0.5-2.8) 0.622 Characteristic JSF vs. ST ([double dagger]) OR (95% CI) p value Chief complaint Fever 2.0 (0.7-5.6) 0.165 Rash 2.2 (1.0-4.7) 0.053 Eschar Not applicable 1.000 ([section]) Headache 0.2 (0-1.4) 0.101 Fatigue 0.5 (0.1-1.6) 0.233 At history collection Fever 1.5 (0.5-4.6) 0.473 Rash 2.0 (0.9-4.3) 0.664 Eschar 0.3 (0-2.2) 0.232 Headache 0.3 (0.1-0.9) 0.026 Fatigue 3.3 (0.4-26.5) 0.256 Physical examination findings BT >37.5[degrees]C 1.1 (0.4-2.5) 0.883 Hypotension ([paragraph]) 5.1 (1.9-13.8) 0.001 Heart rate 0.8 (0.2-3.8) 0.793 >120 bpm Respiratory rate 1.9 (0.8-4.6) 0.174 >20/min Altered mental 2.4 (0.8-7.2) 0.121 status Rash Not applicable 0.597 ([section]) Localized Not applicable 1.000 ([section]) Purpura 36.1 <0.001 (10.1-128.3) Palms/soles 70.3 <0.001 (21.0-235.3) Eschar 1.2 (0.3-4.2) 0.801 Lung involv # 2.8 (1.1-7.0) 0.031 * BT, body temperature; involve, involvement; JSF, Japanese spotted fever; non-R, nonrickettsial diseases; OR, odds ratio; ST, scrub typhus. ([dagger]) Non-R = reference. ([double dagger])ST = reference. ([section]) Fisher exact tests. ([paragraph]) Systolic blood pressure <90 mm Hg or vasopressor usage. # Lung rales with pulmonary infiltrative shadow. Table 3. Laboatory and treatment data for patiients with JSF, ST, and nonrickettsial diseases, central Japian, 2004-2015 * Characteristic JSF, ST, Non-R, no. (%), no. (%), no. (%), n = 31 n = 188 n = 97 Laboratory data Leukocytes 5 (16) 23 (12) 42 (45) >9,800/[micro]L Hb <11 g/dL (F) 5 (16) 29 (16) 46 (49) or <13.5 g/dL (M) Platelets 22 (71) 59 (32) 28 (30) <130,000/[micro]L Albumin <3.4 g/dL 14 (61) 37 (29) 31 (55) AST >33 IU/L 29 (94) 154 (83) 46 (50) ALT >42 IU/L 16 (52) 100 (54) 42 (46) LDH >229 IU/L 30 (97) 179 (97) 70 (78) Total bilirubin 9 (29) 13 (7) 15 (17) >1.0 mg/dL Direct bilirubin 4 (22) 7 (5) 16 (28) >0.4 mg/dL Creatine kinase 19 (66) 46 (29) 21 (28) >150 IU/L BUN >22 mg/dL 15 (48) 35 (19) 20 (22) Creatinine >1.2 mg/dL 11 (35) 22 (12) 7 (8) Sodium <135 mEq/L 24 (77) 71 (39) 16 (17) Chloride <98 mEq/L 17 (55) 37 (22) 15 (16) CRP >10 mg/dL 16 (52) 32 (18) 34 (40) Urine protein 27 (87) 116 (75) 34 (62) Urine blood 29 (94) 122 (79) 31 (56) Treatment and prognosis Duration of 16 (59) 74 (39) 24 (27) illness ([section]) <5 d Treatment: 31 (100) 180 (99) 42 (91) MINO/DOXY Delayed 11 (37) 17 (13) 30 (67) defervescence # Hospitalization 28 (90) 104 (55) 80 (82) 30-d mortality 0 1 (1) 2 (2) Characteristic JSF vs. non-R ([dagger]) OR (95% CI) p value Laboratory data Leukocytes 0.2 (0.1-0.7) 0.006 >9,800/[micro]L Hb <11 g/dL (F) 0.2 (0.1-0.6) 0.002 or <13.5 g/dL (M) Platelets 5.7 (2.3-13.9) <0.001 <130,000/[micro]L Albumin <3.4 g/dL 1.3 (0.5-3.4) 0.653 AST >33 IU/L 14.5 (3.3-64.3) <0.001 ALT >42 IU/L 1.3 (0.6-2.9) 0.566 LDH >229 IU/L 8.6 (1.1-66.8) 0.040 Total bilirubin 2.0 (0.8-5.1) 0.166 >1.0 mg/dL Direct bilirubin 0.8 (0.2-2.6) 0.652 >0.4 mg/dL Creatine kinase 4.9 (2.0-12.2) 0.001 >150 IU/L BUN >22 mg/dL 3.4 (1.4-8.0) 0.006 Creatinine >1.2 mg/dL 6.7 (2.3-19.4) <0.001 Sodium <135 mEq/L 16.3 (6.0-44.3) <0.001 Chloride <98 mEq/L 6.2 (2.5-15.3) <0.001 CRP >10 mg/dL 1.6 (0.7-3.7) 0.266 Urine protein 4.2 (1.3-13.6) 0.018 Urine blood 11.2 (2.4-51.8) 0.002 Treatment and prognosis Duration of 4.0 (1.6-9.8) 0.002 illness ([section]) <5 d Treatment: Not applicable 0.144fl MINO/DOXY Delayed 0.3 (0.1-0.8) 0.012 defervescence # Hospitalization 2.0 (0.5-7.3) 0.302 30-d mortality Not applicable 1.000 ([section]) Characteristic ST vs. non-R ([dagger]) OR (95% CI) p value Laboratory data Leukocytes 0.2 (0.1-0.3) <0.001 >9,800/[micro]L Hb <11 g/dL (F) 0.2 (0.1-0.3) <0.001 or <13.5 g/dL (M) Platelets 1.1 (0.6-1.8) 0.806 <130,000/[micro]L Albumin <3.4 g/dL 0.3 (0.2-0.6) 0.001 AST >33 IU/L 4.8 (2.8-8.4) <0.001 ALT >42 IU/L 1.4 (0.8-2.3) 0.204 LDH >229 IU/L 8.5 (3.3-22.1) <0.001 Total bilirubin 0.4 (0.2-0.8) 0.016 >1.0 mg/dL Direct bilirubin 0.1 (0.1-0.4) <0.001 >0.4 mg/dL Creatine kinase 1.2 (0.6-1.9) 0.861 >150 IU/L BUN >22 mg/dL 0.8 (0.5-1.6) 0.58 Creatinine >1.2 mg/dL 1.6 (0.7-4.0) 0.277 Sodium <135 mEq/L 3.0 (1.6-5.6) <0.001 Chloride <98 mEq/L 1.4 (0.7-2.7) 0.302 CRP >10 mg/dL 0.3 (0.2-0.6) <0.001 Urine protein 1.8 (1.0-3.5) 0.068 Urine blood 2.9 (1.5-5.5) 0.002 Treatment and prognosis Duration of 1.8 (1.0-3.1) 0.039 illness ([section]) <5 d Treatment: 17.1 (1.9- 0.012 MINO/DOXY 157.4) Delayed 0.1 (0-0.2) <0.001 defervescence # Hospitalization 0.3 (0.1-0.5) <0.001 30-d mortality 0.3 (0-3.0) 0.287 Characteristic JSF vs. ST ([double dagger]) OR (95% CI) p value Laboratory data Leukocytes 1.4 (0.5-3.9) 0.556 >9,800/[micro]L Hb <11 g/dL (F) 1.0 (0.4-2.9) 0.939 or <13.5 g/dL (M) Platelets 5.3 (2.3-12.2) <0.001 <130,000/[micro]L Albumin <3.4 g/dL 3.8 (1.5-9.6) 0.004 AST >33 IU/L 3.0 (0.7-13.3) 0.145 ALT >42 IU/L 0.9 (0.4-2.0) 0.824 LDH >229 IU/L 1.0 (0.1-8.7) 0.996 Total bilirubin 5.2 (2.0-13.6) 0.001 >1.0 mg/dL Direct bilirubin 5.2 (1.3-19.9) 0.017 >0.4 mg/dL Creatine kinase 4.6 (2.0-10.7) <0.001 >150 IU/L BUN >22 mg/dL 4.0 (1.8-8.9) 0.001 Creatinine >1.2 mg/dL 4.1 (1.7-9.6) 0.001 Sodium <135 mEq/L 5.4 (2.2-13.2) <0.001 Chloride <98 mEq/L 4.4 (2.0-9.7) <0.001 CRP >10 mg/dL 5.0 (2.2-11.1) <0.001 Urine protein 2.3 (0.7-6.9) 0.148 Urine blood 3.9 (0.9-17.3) 0.071 Treatment and prognosis Duration of 2.2 (1.0-5.1) 0.054 illness ([section]) <5 d Treatment: Not applicable 1.000 ([paragraph]) MINO/DOXY Delayed 3.8 (1.5-9.3) 0.004 defervescence # Hospitalization 7.5 (2.2-25.7) 0.001 30-d mortality Not applicable 1.000 ([paragraph]) * ALT, alanine aminotransferase; AST, aspartate aminotransferase; BT, body temperature; BUN, blood urea nitrogen; CRP, C-reactive protein; DOXY, doxycycline; F, female patients; Hb, hemoglobin; JSF, Japanese spotted fever; LDH, lactate dehydrogenase; M, male patients; MINO, minocycline; non-R, nonrickettsial diseases; OR, odds ratio; ST, scrub typhus. ([dagger]) Non-R = reference. JST = reference. ([section]) Duration from the onset of symptoms to the first diagnostic test. ([paragraph]) Fisher exact tests. # >3 d to decline of fever <37.3[degrees]C.
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|Author:||Sando, Eiichiro; Suzuki, Motoi; Katoh, Shungo; Fujita, Hiromi; Taira, Masakatsu; Yaegashi, Makito; A|
|Publication:||Emerging Infectious Diseases|
|Date:||Sep 1, 2018|
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